Microtubules are an essential component of the cytoskeleton. Agents that disrupt microtubule dynamics within the cell have the potential of arresting cell division and cell proliferation (anti-mitotic agents) and consequentially, acting as anticancer agents. Two types of such agents have been identified. One class inhibits the polymerization of α- and β-tubulin, to microtubules, and is exemplified by compounds such as colchicines 1 and vinca alkaloids 2 (FIG. 26), some of which are clinically used anticancer drugs. In contrast, the second class of anti-mitotic agents accelerates the polymerization of tubulin to microtubules and stabilizes them, thus inhibiting their depolymerization, an essential process during cell division. This second class is commonly referred to as microtubule-stabilizing agents. Paclitaxel (Taxol®) 3 (FIG. 26), initially isolated from the Pacific Yew tree, Taxus bravifolia, was the first of its kind reported and is already in clinical use.
A number of limitations are encountered in the clinical use of paclitaxel. One major limitation is its susceptibility to multiple drug-resistance. Several other compounds possessing the same mechanism of action as paclitaxel have been reported since then. Epothilones 4 (FIG. 27), originally isolated from the myxobacterium Sorangium cellulosum, constitute one such class. They are competitive inhibitors of paclitaxel binding and have been shown to compete for the same or overlapping binding sites on microtubules. From the point of view of anticancer properties, they possess a number of advantages over paclitaxel. Prominent among them is their activity against multiple drug resistant cell lines, which are resistant to paclitaxel.
Extensive studies on structure-activity relationship (SAR) of epothilones have been reported. Many analogues have been synthesized with the aim of improving the pharmacological profile of epothilones. A few epothilone analogues are in various stages of clinical development. Based on SAR studies, the structure of epothilone molecule has been divided into three main sectors (FIG. 28), namely: i) the acyl sector (sector 1); ii) the alkyl sector (sector 2); and, iii) the aryl sector (sector 3). The acyl sector has been shown to be critical for biological activity and is not amenable to major chemical modification, whereas the alkyl and the aryl sectors can accommodate some degree of chemical modification without losing biological activity. Further, the macrolactone ring has been reported to be important for biological activity, as open-chain analogues synthesized were inactive.
Despite the promising therapeutic utility of the epothilones, it would be desirable to investigate additional analogues as well as additional synthetic methodologies for the synthesis of existing epothilones, and analogues thereof, as well as novel analogues thereof.
In particular, given the interest in the therapeutic utility of this class of compounds, it would also be desirable to develop methodologies capable of providing significant quantities of any epothilones, or those described herein, for clinical trials and for large-scale preparation.
Due to the increasing interest in epothilones as anti-cancer agents, novel analogues of these compounds are needed and desired to more fully develop their therapeutic potential.